Retinal ganglion cell (RGC) death is the primary cause of irreversible blindness in Open Angle Glaucoma (OAG) and most optic neuropathies. The goal of this project is to prevent blindness in these diseases by obtaining the information needed to understand the etiology of RGC vulnerability, and use this understanding to develop approaches that prevent cell death. Our objective is determining RGC susceptibility to stressors such as IOP elevation, metabolic load, and neurotrophic factor (NT) deficiency in mouse models of glaucoma and optic neuropathy during the stage of progressive RGC dysfunction preceding death (critical period). Our central hypothesis is that RGC death is the result of failure of autoregulatory/adaptive processes that can no longer sustain normal RGC homeostasis, resulting in loss of RGC electrical responsiveness. During the critical period, RGC responsiveness is modifiable (plastic) upon stressors such as IOP, metabolic demand and NT support, thus providing a rationale and a target for therapeutic intervention. Using innovative methods, we will acutely modulate the levels of these stressors and simultaneously assess modifiability of RGC electrical responsiveness over time using pattern electroretinogram (PERG) and visual evoked potential (VEP). We will also use state-of-the-art optical coherence tomography (OCT) to serially monitor thickness of inner retinal layers, as well as retinal immunohistochemistry at endpoint. We will attain our goal and objective by accomplishing the following aims: 1) Test the hypothesis that RGC plasticity occurs in a specific time window in mouse models of glaucoma and optic neuropathy. Models will be the Myoc transgenic mouse of glaucoma, the ND4 transgenic mouse of multiple sclerosis, and the MOG-specific TCR transgenic mouse of optic neuritis. Controls will be corresponding non-pathological congenic mice. We will non-invasively alter either IOP with changes of body posture, or the metabolic demand with flickering light, and will measure corresponding changes of the PERG/VEP signal that precede loss of OCT signal; 2) Test the hypothesis that RGC plasticity is inducible in mouse models of chronic NT deficiency. We will perform unilateral lesions of the superior colliculus (SC) in C57BL/6J and DBA/2J mice and will quantify changes of the PERG and OCT signal in each eye. We will also induce IOP and metabolic stress in SC-lesioned mice to quantify acquired susceptibility of the PERG signal. Successful completion of our research will establish a new conceptual model of RGC susceptibility, and will improve our technical capability of detecting diseases' onset, monitoring their progression and the effect of treatment, eventually changing clinical practice. This will represent a significant advancement in the field and will be influential on future research on glaucoma and other neurodegenerative diseases involving RGC.